The present invention relates to a process for preparing certain 3-hydroxy-ML-236B derivatives known as M-4 and M-4', as well as salts and esters of these compounds.
ML-236B, which can exist in the form of an acid (known as "ML-236B carboxylic acid") or a lactone (known as "ML-236B lactone"), is disclosed in United Kingdom Patent Specification No. 1,453,425 and, in its lactone form, has the formula: ##STR2##
Subsequently, United Kingdom Patent Specification No. 1,555,831 disclosed a variety of salts and esters of ML-236B. ML-236B and its salts and esters were found to inhibit the biosynthesis of cholesterol by competing with 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the rate-determining enzyme for chloesterol biosynthesis; these compounds were thus found to exhibit a very marked ability to reduce serum cholesterol levels.
Subsequently, certain 3-hydroxy-ML-236B derivatives were isolated as products of the animal metabolism of ML-236B lactone and similar derivatives were found to be produced by the enzymatic hydroxylation of ML-236B lactone or carboxylic acid or salts or esters thereof, effected by means of various microorganisms of the genera Absidia, Cunninghamella, Syncephalastrum, Streptomyces, Mucor, Rhizopus, Zygorinchus, Circinella, Actinomucor, Gongronella, Phycomyces, Mortierella, Pycnoporus and Rhizoctonia. These processes are disclosed in U.S. Pat. No. 4,346,227, filed 5th June 1981, by A. Terahara and M. Tanaka and the compounds thus produced are described in that patent application as M-4, M-4', IsoM-4 and IsoM-4'. These compounds were found to have an ability to inhibit the biosynthesis of cholesterol which is at least comparable with and, in some instances, substantially exceeds that of ML-236B itself.
ML-236B and its derivatives, including the M-4 and M-4' compounds, are thus of therapeutic value for the treatment of hyperlipaemia and the prophylaxis of arteriosclerosis.